Intravenous amino acid solutions are known and are approved for clinical administration to patients requiring intravenous nutrition. They are usually administered along with glucose, fat, electrolytes, and vitamins. The present commercial intravenous amino acid solutions are formulated in accordance with the amino acid requirements of man as delineated by William C. Rose and associates. See, Rose, Fed. Proc. 8, 546 (1949); Rose et al., J. Biol. Chem., 217, 987 (1955). U.S. Pat. No. 3,764,703 discloses the use of mixtures of essential amino acids combined in proportions according to the pattern of Rose for administration to patients suffering from reduced kidney function, uremia. According to this patent, the essential amino acids may be administered for the treatment of uremic conditions either intravenously or orally, with resultant lowering of blood urea nitrogen and increased nitrogen retention.
U.S. Pat. No. 3,832,465 discloses intravenous infusion solutions of amino acids containing both essential and nonessential amino acids, which are characterized by having at least 40%, and preferably from 42 to 68%, of the total amino acids comprising the branched chain amino acids, leucine, isoleucine, and valine. It is stated that the branched chain amino acids are metabolized by major pathways not involving the liver, and that therefore they can be intravenously administered in larger proportions than those amino acids dependent on the metabolic action of the liver.
Prior to the present invention, as far as is known, no specially formulated amino acid mixtures have been proposed for administration to liver diseased patients either for therapeutic effects or for nutritional purposes. Malnutrition is a serious problem with such patients. The patient with cirrhosis generally eats poorly, and such patients are usually placed on protein-restricted diets. Liver disease interferes with normal protein utilization. Moreover, encephalopathy leading to coma and death is associated with advanced cirrhosis and other serious liver disease. By restricting protein intake, the tendency of the liver diseased patients to develop hepatic encephanlopathy may be reduced. However, such limitation of protein intake further contributes to the malnutrition of the patient.
Rose pattern intravenous solutions of amino acids have been administered to liver diseased patients both for nutritional support and experimentally for study of the effect on the patient's plasma amino acid levels. Such studies have shown that the content of amino acids in the plasma of liver diseased patients is seriously distorted, the branched chain amino acids (isoleucine, leucine, and valine) being lower than normal, while methionine and the aromatic amino acids phenylalanine and tryptophan are higher than normal. See Fischer et al., Am. J. Surg., 127, 40 (Jan. 1974), and references cited therein. The amino acid formulations administered by Fischer et al. included solutions containing only essential amino acids, as well as solutions containing both essential and nonessential amino acids. The plasma levels of the branched chain essential amino acids and methionine were consistently decreased, while there was a consistent elevation above normal of phenylalanine and methionine. However, the tryptophan levels were near normal or only slightly elevated. With the mixture of essential and nonessential amino acids, tyrosine was considerably above the normal level, and was found to be elevated, although to a lesser extent, even with the mixture containing only the eight essential amino acids.
An attempt was made to increase the low plasma levels of branched chain amino acids by increasing the amount infused up to two and one half times the minimal daily requirements recommended by Rose for isoleucine, leucine, and valine. Such high level infusion of branched chain amino acids, however, failed to correct the low concentrations of these amino acids in the patients' plasma. The metabolic consequence of low plasma levels of branched chain amino acids is not known, nor has anyone previously proposed a relationship between plasma levels of branched chain amino acids and hepatic encephanlopathy.
It has been suggested that an excess of phenylalanine may inhibit the transport of tyrosine to the brain. Guroff et al., J. Biol. Chem. 237, 803 (1962). Further, it is known that tyrosine is important for the synthesis of some of the normal catecholamine neurotransmitters in the brain. It has also been suggested that the level of serotonin in the brain may be related to the association between plasma tryptophan, as opposed to plasma phenylalanine, tyrosine, and the branched chain amino acids. Fernstrom, et al., Science, 178, 414 (1972). However, earlier studies tended to establish that the principle factor modulating brain tryptophan was the ratio of plasma tryptophan to the sum of all of the plasma amino acids. See Perez-Cruet et al., Nature, 248, 693 (1974).
In accordance with the present invention, the amount administered of phenylalanine alone, or phenylalanine and tyrosine in combination, or tyrosine alone is controlled in relation to the total of the essential branched chain amino acids, specifically isoleucine, leucine, and valine to achieve metabolically acceptable levels of plasma phenylalanine and tyrosine. It appears that the formulations of the present invention permit adequate transfer of tyrosine to the brain, and that there is no serious inhibition of such transport due to excessive plasma phenylalanine. Further, the amount of phenylalanine administered may be reduced, or in some embodiments eliminated entirely, if the phenylalanine in the amino acid mixture is partially replaced by tyrosine. Such replacement is limited by the low water solubility of tyrosine. The tyrosine can be supplemented by more water soluble tyrosine derivatives, providing the derivative is convertible by the body to tyrosine.
The experimental work leading to the present invention has also indicated that the relative proportions of the essential branched chain amino acids should be controlled in relation to the proportion of tryptophane administered. By proper balancing of the proportions of isoleucine, leucine, and valine to tryptophan, it is believed that the transfer of excessive tryptophan to the brain can be avoided. This is desirable since tryptophan is converted by the brain to serotonin, which would be expected to complicate hepatic encephalopathy. It therefore appears that the quantity of amino acid administered for nutritional utilization by the patient can be significantly increased while therapeutically maintaining normal brain function. In general, all of the plasma amino acids may compete with the plasma tryptophan for transport to the brain. However, what seems to be of importance for the purpose of the present invention is that phenylalanine and tryosine are relatively less competitive with tryptophane for entry into the brain compared to the branched chain essential amino acids.
It should be understood that the foregoing mechanisms are not known with complete certainty. Further, diseased livers do not respond predictably in all cases. Nevertheless, the available experimental evidence, strongly indicates that administration of the amino acid formulation of this invention can be expected to therapeutically reduce the incidence and severity of hepatic encephalopathy, while providing more nearly adequate nutritional support for the patients suffering from liver disease. The treatment of hepatic encephalopathy should also be clinically attainable. Moreover, by achieving more nearly adequate nutrition, while avoiding the complications of encephalopathy and coma, an opportunity is provided for improved liver function to develop. It is known that the liver has remarkable power to hypertrophy or regenerate. Consequently, if the patient can be maintained over a sufficient period of time with adequate nutrition, the liver may repair and fully recover.
The formulations of this invention may include both essential and nonessential amino acids, or only essential amino acids, but the inclusion of some nonessential amino acids is desirable. With respect to nutritional support, resultant plasma amino acid levels, brain function, and therapeutic benefits there is a complex interrelationship between the amino acid formulations of this invention. In addition to the considerations discussed above, therefore, the relative proportions of all of the amino acids incorporated, essential and nonessential, including amino acids which may be optionally included, are specified in terms of their respective molar ranges.